A theoretical analysis of the genomic structure of the Ebola virus Zaire strain reveals the existence of several open reading frames (ORFs) containing large numbers of in-frame UGA codons. This clustering of UGA codons is very unlikely to have arisen by chance, and raises the possibility that these ORFs may encode selenoproteins, since, in addi-tion to its usual role as a stop codon, UGA can under certain conditions encode selenocysteine. The other major require-ment for selenocysteine insertion at UGA codons appears to be met in this case, due to the presence of selenocysteine insertion sequences (SECIS) in stable stem-loop structures in the appropriate Ebola Zaire mRNAs. Specifically, there is a SECIS in the 3'-untranslated region of the nucleoprotein mRNA, where the largest potential seleno-proteins are encoded, one of which may contain up to 16 selenium atoms per molecule. The expression of this hypothetical protein could impose an unprecedented se-lenium demand upon the host, potentially leading to severe lipid peroxidation and cell membrane destruction. This could also con-tribute to the characteristic hemorrhaging caused by intravascular blood clotting, due to the thrombotic effect of Se deficiency. The possibility that this gene might contribute to the extreme pathogenicity of the Zaire strain of Ebola virus by this mechanism is also consistent with the observation that this po-tential selenoprotein gene is not present in the Ebola Reston strain, which was not pathogenic in humans.